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TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy

Jia-Ming Xie1, Bin Li2, Hong-Pei Yu1

  • 1Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Cancer Research
|August 3, 2014
PubMed

Insights

The p53-induced glycolysis and apoptosis regulator (TIGAR) protein impacts cancer cell survival by inhibiting both apoptosis and autophagy. Silencing TIGAR enhances chemotherapy effectiveness by increasing ROS and apoptosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Metabolism

Background:

  • The p53-induced glycolysis and apoptosis regulator (TIGAR) is known to inhibit glycolysis, leading to increased intracellular NADPH, reduced reactive oxygen species (ROS), and suppressed autophagy.
  • TIGAR's dual role in regulating both apoptosis and autophagy suggests a complex influence on cancer cell survival, particularly in response to chemotherapy.

Purpose of the Study:

  • To investigate the dual impacts of TIGAR on cancer cell survival, specifically its inhibition of apoptosis and autophagy.
  • To determine the effect of TIGAR modulation on cancer cell response to the anticancer drug epirubicin.

Main Methods:

  • Liver and lung cancer cells were treated with epirubicin, and TIGAR levels were monitored.
  • TIGAR was silenced, and its effects on ROS levels, apoptosis, autophagy, and the mTOR pathway were assessed.
  • NADPH or N-acetyl cysteine were ectopically added to evaluate their role in blocking TIGAR silencing effects.
  • Mouse xenograft tumor assays were performed to assess tumorigenicity and chemosensitivity.

Main Results:

  • Epirubicin treatment increased TIGAR levels in a dose- and time-dependent manner.
  • TIGAR silencing enhanced epirubicin-induced ROS production and apoptosis, effects mitigated by NADPH or N-acetyl cysteine.
  • TIGAR silencing also increased epirubicin-induced autophagy activation and licensed epirubicin-mediated mTOR pathway inactivation.
  • Inhibition of autophagy in TIGAR-silenced cells potentiated epirubicin-induced apoptosis.
  • Reduced tumorigenicity and increased chemosensitivity were observed in mouse xenograft models with TIGAR silencing.

Conclusions:

  • TIGAR plays a dual role in cancer cells by inhibiting both apoptosis and autophagy, thereby impacting tumor cell survival during chemotherapy.
  • TIGAR silencing sensitizes cancer cells to chemotherapy by promoting ROS accumulation and apoptosis, and enhancing autophagy.
  • Targeting TIGAR may represent a viable strategy to improve the efficacy of anticancer therapies like epirubicin.

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